B cell memory - defined as antigen-specific B cells and plasma cells that are maintained over the long-term - is essential for the success of most current vaccines, including those to influenza. However, our understanding of how and where these cells are generated and maintained is incomplete. Thus, it is difficult to rationally design new vaccines that will efficiently elicit B cell memory or to intervene in situations in which memory B cells contribute to disease. Although memory B cells have been phenotypically identified in humans, their counterparts in mice have been, until recently, more difficult to identify. Thus, while we have some idea of what memory B cells look like, particularly in human blood, we have much less understanding of the memory B cells that are maintained in tissues. For example, memory B cells appear to be maintained in the lungs of mice (and presumably humans) that have been previously infected with influenza. However, we have no idea how these memory cells differ from their counterparts that circulate in the blood. This proposal will define the characteristics of central memory B cells (in secondary lymphoid organs) and effector memory B cells in peripheral non-lymphoid organs, such as the lung. We will also determine the mechanisms that maintain memory B cells and plasma cells in the lung, define the timing of memory B cell recruitment (or generation) to the lung, determine the specificities and longevity of the memory B cells in the lung compared to other sites and test whether the presence of Bronchus Associated Lymphoid Tissue (BALT) alters the composition, lifespan or activity of memory B cells in the lung. Together, these experiments will determine the phenotype and more importantly, the function of effector memory B cells that are maintained in peripheral tissues. Thus, these results will inform the rational design of vaccines that protect the respiratory tract and lead to therapies that enhance or curtail the generation and maintenance of memory B cells in the lung. PUBLIC HEALTH RELEVANCE: The experiments in this project will facilitate the identification and characterization of central and effector memory B cells that reside in lymphoid organs or peripheral non-lymphoid tissues. Given that successful vaccination against influenza is dependent on the generation of long-lived memory B cells and plasma cells, these experiments will help us to develop more effective vaccines against influenza and other infectious diseases.